title: Tyrosine phosphorylation of HuR by JAK3 triggers dissociation and degradation of HuR target mRNAs.
abstract: In response to stress conditions, many mammalian mRNAs accumulate in stress granules (SGs) together with numerous RNA-binding proteins that control mRNA turnover and translation. However, the signaling cascades that modulate the presence of ribonucleoprotein (RNP) complexes in SGs are poorly understood. Here, we investigated the localization of human antigen R (HuR), an mRNA-stabilizing RNA-binding protein, in SGs following exposure to the stress agent arsenite. Unexpectedly, the mobilization of HuR to SGs was prevented through the activation of Janus kinase 3 (JAK3) by the vitamin K3 analog menadione. JAK3 phosphorylated HuR at tyrosine 200, in turn inhibiting HuR localization in SGs, reducing HuR interaction with targets SIRT1 and VHL mRNAs, and accelerating target mRNA decay. Our findings indicate that HuR is tyrosine-phosphorylated by JAK3, and link this modification to HuR subcytoplasmic localization and to the fate of HuR target mRNAs.
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Je-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Subramanya
authors.initials: S
authors.lastname: Srikantan
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D003594:Cytoplasmic Granules / Q000378:metabolism; D051959:ELAV Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D051959:ELAV Proteins; D012333:RNA, Messenger; D014443:Tyrosine; D053616:Janus Kinase 3